Momelotinib Shows Potential to Expand Treatment for Myelofibrosis

Aaron T. Gerds, MD, MS

Treatment options for patients with myelofibrosis has begun to widen with the introduction of more JAK inhibitors to the clinic for patients with myelofibrosis who are anemic.

In an interview with Targeted OncologyTM, Aaron T. Gerds, MD, MS, discusses recent results from the phase 3 MOMENTUM trial (NCT04173494) that showed continued responses and tolerability after 48 weeks of treatment with the JAK1/JAK2 inhibitor momelotinib (CYT387). These data were initially presented at the American Society of Hematology (ASH) 2022 Annual Meeting.¹ There, Gerds presented data that showed anemic patients with myelofibrosis was consistent with an initial analysis of patients on momelotinib vs those on for 24 weeks and there were no new safety signals. In the study arm, 93 out of 130 patients continued in the week 48 open-label period, and 41 out of 65 first given danazol crossed over to the momelotinib arm.

In an interview with Targeted Oncology, Gerds, assistant professor in Medicine (Hematology and Medical Oncology) at the Cleveland Clinic, discusses where momelotinib fits in the landscape of JAK inhibitors for patients with myelofibrosis among a field of FDA approved therapies like ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo).²

What was the design of the MOMENTUM study?

MOMENTUM is a phase 3 randomized trial pitting momelotinib vs danazol for patients with myelofibrosis. The study selected patients who had previous JAK inhibitor exposure, were anemic, significantly symptomatic, and had enlarged spleens. It was looking to see if momelotinib was a better option for these patients. Danazol was chosen as a comparator, because it is an active agent in remedying anemia in these folks, while momelotinib is a special JAK inhibitor that not only can shrink spleens and improve symptom burden, but it can also have a potential effect on anemia through inhibition of ACVR1.

Momelotinib molecule | Image Credit: © Circe - www.stock.adobe.com

What were the main results from the trial?

The week 24 primary endpoints were already reported...and this was the updated results from week 48. At week 24, patients were allowed to cross over to open label momelotinib, even if they were on the momelotinib arm or the danazol arm. It is basically an open label extension at this point, but we get to continue data. The first key take home point from the data we presented was that there were no new toxicities or safety signal seen. So, the data was consistent with what we saw in the original 24-week analyses. This is, of course, incredibly important when you think about the fact that these folks might be on this medication for a long time. Moreover, the responses were quite durable in patients who responded at week 24 continue to respond through week 48, whether we're talking about transfusion independence, spleen volume response, or symptom burden improvement.

A curiosity is, some of the patients who did not have an original symptom response during the first 24 weeks did [have a symptom] during the next 24 weeks, indicating that maybe additional therapy might be beneficial. Lastly, we looked at different platelet count cut offs from 150 to 150,000. The response rates were quite similar no matter what the platelet count threshold was in that ad hoc analysis, and that's important because thrombocytopenia often occurs with anemia. So, if you have a drug that treats anemia you also want to have efficacy in patients who are thrombocytopenic.

How does momelotinib compare with other JAK inhibitors in this space?

There are currently 3 approved JAK inhibitors for the treatment of [patients with] myelofibrosis, ruxolitinib, fedratinib, and pacritinib. They all have different advantages and disadvantages. As we get more and more therapies, the key is looking at the subtle differences between these therapies to choose the best [treatment] for the individual sitting in front of you. Ruxolitinib has been around the longest and is quite effective at shrinking spleens and improving symptom burden. There is some inkling in long term pooled analyses that it improves survival as well, but I suspect that's true for all and JAK inhibitors. Fedratinib does have different AEs than ruxolitinib, as we do see a little bit more gastrointestinal toxicity with fedratinib, but over time, we've become adept at preemptively treating that. Fedratinib can [also] work notably well in patients who have already received ruxolitinib, which is a key piece of data that supports its use.

pacritinib has been studied in many patients through a number of trials. The label for pacritinib focuses on patients with platelet counts less than 50,000, because you can safely deliver full JAK inhibitor therapy to these folks that would otherwise be limited by the thrombocytopenia for ruxolitinib in fedratinib. So, they all kind of have positions [in this space, and now with momelotinib we're going to have to reshuffle the deck on how we use these JAK inhibitors. It'll be up to those of us in the field in getting these detailed results from all the different clinical trials [to sort out which JAK inhibitor we're going to use were.

What are some toxicities to look out for with momelotinib and other JAK inhibitors?

There is continuation [of treatment] beyond week 48 [in the MOMENTUM study]. So, we want to keep following these patients for the response duration, but also signals for new toxicity. There was an early concern in the development of momelotinib for peripheral neuropathy. We've seen very little peripheral neuropathy through week 48, but I think it's important to keep watching these folks to see if it emerges later. Secondly, with all JAK inhibitors, we're concerned about major cardiac AEs, and not only with JAK inhibitors for [patients with] myelofibrosis, but for rheumatologic diseases and others [as well].

Are there other updates for the treatment of patients with myelofibrosis that excite you?

We always look forward to having new agents to help treat our patients. The kind of continued momentum, if you will, in the combination therapy studies [has had the] the biggest buzz throughout. There are some other exciting compounds that are entering trials like Selinexor [Xpovio], [which is] an interesting compound that we're seeing some intriguing very early results...and we're cautiously optimistic that could be beneficial. Other drugs like navtemadlin [KRT-232]are being developed,3 but other creative ways in how to not only improve symptoms and spleen size, and [patients'] quality of life, but get after the disease as well. It's really creating a lot of buzz going for this, dare I say, disease modification in myelofibrosis.

_References:

_{1. Gerds T, Mesa R, Vannucchi A, et al. Updated Results from the Momentum Phase 3 Study of Momelotinib (MMB) Versus Danazol (DAN) in Symptomatic and Anemic Myelofibrosis (MF) Patients Previously Treated with a JAK Inhibitor. Blood. 2022;140(1):1514-1517. doi:10.1182/blood-2022-162783}

_{2. Shawky AM, Almalki FA, Abdalla AN, et al. A Comprehensive Overview of Globally Approved JAK Inhibitors. Pharmaceutics. 2022;14(5):1001. doi:10.3390/pharmaceutics14051001}

_{3. Verstovsek S, Al-Ali HK, Mascarenhas J, et al. BOREAS: a global, phase III study of the MDM2 inhibitor navtemadlin (KRT-232) in relapsed/refractory myelofibrosis. Future Oncol. 2022;18(37): 4059-4069 doi:10.2217/fon-2022-0901}